Neuregulins (NRGs) and their receptors, erbB2, 3 and 4, play a critical role both in cardiovascular development and the function of differentiated cardiovascular tissues, including vascular endothelial cells (Ecs) and cardiac myocytes. During embryogenesis, NRG-1, erbB2, erbB3 and erbB4 are required for proper formation of cardiac structures, as evidenced by the finding that genetic knockout of any one of these molecules results in a cardiac phenotype which is incompatible with development beyond 10 to 13 days after fertilization. Our previous work has shown that NRG-1 can increase proliferation of and lead to in vitro tube formation by diffentiated human vascular endothelial cells. Furthermore, we have demonstrated that local administration of NRG-1 to adult rats can lead to angiogenesis. Administration of NRG-1 to adult rat cardiac myocytes has been shown to promote proliferation, survival, protein synthesis and hypertrophy. These effects of NRG on both angiogenesis and cardiac myocytes make the NRG signaling system an attractive target for treatment of ischemic cardiovascular disease. The proposed research is based on the hypothesis that NRG plays an important role in autocrine regulation of cardiovascular Ecs and in EC paracrine and/or juxtacrine regulation of adjacent myocytes. Specifically, this work will define the known NRG gene products and isoforms expressed by cardiovascular endothelium using both animal tissues and isolated cells in culture. Next, we will investigate factors which affect the synthesis and secretion of NRGs from cardiovascular Ecs using both in vitro and in vivo models. Activation of NRG-induced signaling pathways will be further studied in both Ecs (autocrine) and cardiac myocytes (paracrine). Finally, the role of juxtacrine signaling by membrane-anchored forms of NRG will be explored using targeted NRG mutations. The findings of thisstudy will provide a fundamental basis for understanding the role of NRG signaling in cardiovascular tissues, information which is critical for development of NRG-based treatment strategies for human ischemic cardiomyopathy.